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Information on EC 1.14.11.51 - DNA N6-methyladenine demethylase and Organism(s) Mus musculus and UniProt Accession P0CB42

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IUBMB Comments
Contains iron(II). Catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons, which are specifically enriched on the human X chromosome.
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This record set is specific for:
Mus musculus
UNIPROT: P0CB42
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Word Map
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
N6-methyladenine in DNA
+
+
=
adenine in DNA
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+
+
Synonyms
nmad-1, dna 6ma demethylase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SYSTEMATIC NAME
IUBMB Comments
DNA-N6-methyladenosine,2-oxoglutarate:oxygen oxidoreductase (formaldehyde-forming)
Contains iron(II). Catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons, which are specifically enriched on the human X chromosome.
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
show the reaction diagram
additional information
?
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ALKBH1 prefers bubbled or bulged DNAs as substrate. The middle N6-mA in the 3-nt bulge is efficiently demethylated compared to that in the 3-nt bubble (97% vs. 18% demethylation fraction) and the 1st and 3rd N6-mAs are more resistant to demethylation. N6-mAs deposited in the flexible region of hairpin (DNA stem loop), D-loop and R-loop are efficiently demethylated as in bubble and bulge, while those in cruciform and replication fork are less demethylated. m6rA in RNA hairpin, RNA-RNA bubble and RNA-DNA hybrid bubble can also be demethylated by ALKBH1, as well as 5-methylcytosine at anticodon loop and 1-methyladenosine
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
N6-methyladenine in DNA + 2-oxoglutarate + O2
adenine in DNA + formaldehyde + succinate + CO2
show the reaction diagram
the enzyme catalyses oxidative demethylation of DNA N6-methyladenine, a prevalent modification in LINE-1 transposons
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-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Fe2+
contains Fe2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Iron
H231, D233 and H287 are ligands of the catalytic iron metal
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
ALKBH1 enhances proliferation and inhibits differentiation of C2C12 cells
Manually annotated by BRENDA team
N6-mA levels shows a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
N6-hydroxymethyladenine exists as an oxidized intermediate during N6-mA demethylation by ALKBH1
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ALKB1_MOUSE
389
0
43746
Swiss-Prot
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
43746
x * 43746, calculated from sequence
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 43746, calculated from sequence
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme shows a stretch-out conformation of its Flip1 motif, explaining the observed preference of ALKBH1 for unpairing substrates, in which the flipped N6-mA is primed for catalysis. Structures of ALKBH1 bound to a 21-mer bulged DNA show the need of both flanking duplexes and a flipped base for recognition and catalysis
structure to 3.1 A resolution. The N-terminal domain of the protein forms close contacts with the core catalytic domain and might be responsible for the recognition of nucleic acid substrates. H231, D233 and H287 are ligands of the catalytic iron metal
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D233A
reduced activity of the recombinant mutant protein
K158A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R159A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R160A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R167A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
R169A
mutation of basic residue of Flip1 region, abolishes N6-mA demethylation activity of ALKBH1
S235D
mutation disrupts N6-mA demethylation activity
S235E
mutation disrupts N6-mA demethylation activity
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
during the progression of vascular calcification in a model of chronic kidney disease, increased ALKBH1 expression is linked to decreased 6mA levels
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wu, T.P.; Wang, T.; Seetin, M.G.; Lai, Y.; Zhu, S.; Lin, K.; Liu, Y.; Byrum, S.D.; Mackintosh, S.G.; Zhong, M.; Tackett, A.; Wang, G.; Hon, L.S.; Fang, G.; Swenberg, J.A.; Xiao, A.Z.
DNA methylation on N-adenine in mammalian embryonic stem cells
Nature
532
329-333
2016
Mus musculus (P0CB42)
Manually annotated by BRENDA team
Li, H.; Zhang, Y.; Guo, Y.; Liu, R.; Yu, Q.; Gong, L.; Liu, Z.; Xie, W.; Wang, C.
ALKBH1 promotes lung cancer by regulating m6A RNA demethylation
Biochem. Pharmacol.
189
114284
2021
Homo sapiens (Q13686), Mus musculus (P0CB42)
Manually annotated by BRENDA team
Cai, G.P.; Liu, Y.L.; Luo, L.P.; Xiao, Y.; Jiang, T.J.; Yuan, J.; Wang, M.
Alkbh1-mediated DNA N6-methyladenine modification regulates bone marrow mesenchymal stem cell fate during skeletal aging
Cell Prolif.
55
e13178
2022
Mus musculus (P0CB42)
Manually annotated by BRENDA team
Zhang, M.; Yang, S.; Nelakanti, R.; Zhao, W.; Liu, G.; Li, Z.; Liu, X.; Wu, T.; Xiao, A.; Li, H.
Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA
Cell Res.
30
197-210
2020
Mus musculus (P0CB42)
Manually annotated by BRENDA team
Diao, L.; Xie, S.; Yu, P.; Sun, Y.; Yang, F.; Tan, Y.; Tao, S.; Hou, Y.; Zheng, L.; Xiao, Z.; Zhang, Q.
N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle
Exp. Cell Res.
400
112492
2021
Mus musculus (P0CB42)
Manually annotated by BRENDA team
Ouyang, L.; Su, X.; Li, W.; Tang, L.; Zhang, M.; Zhu, Y.; Xie, C.; Zhang, P.; Chen, J.; Huang, H.
ALKBH1-demethylated DNA N6-methyladenine modification triggers vascular calcification via osteogenic reprogramming in chronic kidney disease
J. Clin. Invest.
131
e146985
2021
Homo sapiens (Q13686), Mus musculus (P0CB42)
Manually annotated by BRENDA team